PROJECT SUMMARY/ABSTRACT One of the major reasons cited for the use of electronic cigarettes (EC) is to reduce harm from smoking. Harm reduction using EC might be accomplished by smoking fewer conventional tobacco cigarettes (TC) per day, or switching completely form TC to EC. To date there are relatively few data on health consequences of EC use for harm reduction. Our laboratory has been conducting research on the clinical pharmacology and toxicology of ECs for several years. Our approach has been intensive investigation of use behaviors, chemical exposures and biological effects of EC compared to TC use in subjects confined to a research ward setting. We propose to use a similar research approach to study harm reduction questions with the use of the newly-developed NIDA Standardized Research E-cigarette (SREC). Our overall goals are two-fold: (1) to compare nicotine and toxicant exposure and pharmacological effects of SREC used alone vs TC; and (2) using scheduled SREC use combined with ad libitum TC use as a model for dual use, to examine the extent to which nicotine and toxicant exposure and biomarkers of potential harm compare with dual use vs TC alone use. The former would inform the effects of total switching, the latter would inform the potential harm reducing effects of smoking fewer TC while using EC. Daily cigarette smokers who are familiar with EC use will be instructed to use only SREC and TC, each for one week at time. On a third week they will be instructed to use SREC on a schedule 8 times per day, and be free otherwise to use either SREC or TC as desired. For the last three days of each week, subjects will be confined to a clinical research unit to ensure strict compliance with product use and for intensive data and biospecimen collection. We will: (1) examine SREC as a nicotine delivery device, including individual variability in nicotine intake and pharmacokinetics, temporal patterns of use and titration of nicotine, compared to TC use; (2) examine subjective effects of SREC use, including relationship of pattern and extent of use and nicotine levels to reward, withdrawal and craving, with comparison to TC use; (3) examine aspects of safety of SREC use (by assessment of cardiovascular and hormonal effects of use and of biomarkers of exposure to potentially toxic constituents); (4) compare nicotine and toxicant exposure, subjective effects and cardiovascular and hormonal effects of TC alone vs dual SREC/TC use (harm reduction assessment) and (5) validate biomarkers that may be useful in distinguishing EC from TC use. The proposed research will provide essential information on the clinical pharmacology and toxicology of SREC, and on the potential for smoking fewer TC per day supported by dual use of SREC to reduce adverse cardiovascular health effects of TC use alone.